HCN1 (O60741) variants and mutations
HCN1 (also known as O60741) is a human protein-coding gene encoding a potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 protein. The protein forms a hyperpolarization-activated channel that conducts both potassium and sodium ions. It contributes to pacemaker currents and the neuronal I(h) current that shapes excitability, and HCN1 variants are associated with developmental epilepsy syndromes. This analysis covers 1,814 HCN1 variants and mutations. Of these, 64% have computational variant effect predictions. Disease context includes Generalized epilepsy with febrile seizures-plus, undetermined early-onset epileptic encephalopathy, and genetic developmental and epileptic encephalopathy. Example HCN1 variants include M1?, G3E, and G3V.
Variant analysis overview
- Gene: HCN1
- Protein: O60741
- UniProt accession: O60741
- Organism: Homo sapiens
- Variants analyzed: 1814
- Variant scope: all variants
- Completed: 2026-07-07
Variant and mutation evidence
- Variant composition: 1,423 unspecified-consequence records; 195 synonymous variants; 170 missense variants; 9 stop-gained variants; 5 in-frame deletions; 7 frameshift variants; 2 in-frame insertions; 1 protein altering variant; 1 splice-region variants; 1 substitution
- Prediction scores: 1,168 variants have prediction scores (64% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Generalized epilepsy with febrile seizures-plus, undetermined early-onset epileptic encephalopathy, genetic developmental and epileptic encephalopathy, early-infantile DEE, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalo, generalized epilepsy with febrile seizures plus, schizophrenia, breast carcinoma, Seizure, Irritability, arthropathy, type 2 diabetes mellitus.
Protein structure and variant hotspots
- Protein features: 6 transmembrane segments; 7 binding sites; 1 post-translational modification sites.
- Structural context: 171 variants have structural context.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, PharmGKB, MaveDB, LitVar.
Notable HCN1 variants
Examples include M1?, G3E, G3V, G4S, G5D, P7R, N8S, S9P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G3E (p.Gly3Glu), gnomAD rs1271471544, REVEL 0.24, CADD 19.80, Uncertain significance, Early-infantile DEE
- G3V (p.Gly3Val), rs1271471544, ClinGen CA359706945, ClinVar RCV006562977, NCI-TCGA TCGA novel, REVEL 0.28, CADD 19.70, Uncertain significance, Early-infantile DEE
- G4S (p.Gly4Ser), Ensembl rs1740007380, REVEL 0.30, CADD 15.90
- G5D (p.Gly5Asp), Ensembl rs1740007331, REVEL 0.33, CADD 20.20
- P7R (p.Pro7Arg), rs1156299203, ClinGen CA359706921, ClinVar RCV004066199, ClinVar RCV006612032, REVEL 0.30, AlphaMissense 0.07, Conflicting interpretations, Early-infantile DEE; Inborn genetic diseases
- N8S (p.Asn8Ser), gnomAD rs1445930484, REVEL 0.22, CADD 20.10
- S9P (p.Ser9Pro), rs1554040148, ClinGen CA359706909, ClinVar RCV006607411, Ensembl rs1554040148, REVEL 0.40, CADD 23.90, Likely benign, Early-infantile DEE
- S9Y (p.Ser9Tyr), TOPMed rs1282790075, REVEL 0.42, AlphaMissense 0.08
- S10L (p.Ser10Leu), TOPMed rs1453769463, REVEL 0.33, CADD 19.50
- S13C (p.Ser13Cys), rs1740006768, ClinGen CA359706882, ClinVar RCV006560443, REVEL 0.34, CADD 21.50, Uncertain significance, Early-infantile DEE
- S13R (p.Ser13Arg), TOPMed rs1194673599, gnomAD rs1194673599, REVEL 0.32, CADD 20.70
- R14Q (p.Arg14Gln), TOPMed rs1252734883, REVEL 0.28, CADD 23.90
- D15G (p.Asp15Gly), Ensembl rs2112109748, REVEL 0.29, CADD 22.30
- D16N (p.Asp16Asn), rs1283834151, ClinGen CA359706861, ClinVar RCV006464394, gnomAD rs1283834151, REVEL 0.27, AlphaMissense 0.07, Uncertain significance, Early-infantile DEE
- D16Y (p.Asp16Tyr), gnomAD rs1283834151, REVEL 0.37, AlphaMissense 0.07, Uncertain significance
- G17D (p.Gly17Asp), gnomAD rs1740006450, REVEL 0.33, CADD 23.20
- G17V (p.Gly17Val), NCI-TCGA TCGA novel, REVEL 0.32, CADD 23.10, Variant assessed as somatic; moderate impact.
- S19R (p.Ser19Arg), gnomAD rs1237981237, REVEL 0.16, AlphaMissense 0.13, Uncertain significance, Developmental and epileptic encephalopathy, 24
- F21L (p.Phe21Leu), NCI-TCGA TCGA novel, REVEL 0.14, AlphaMissense 0.72, Variant assessed as somatic; moderate impact.
- F21V (p.Phe21Val), Ensembl rs1740006335, REVEL 0.18, CADD 21.70
- F21Y (p.Phe21Tyr), gnomAD rs1470715710, REVEL 0.14, CADD 18.20
- P22L (p.Pro22Leu), NCI-TCGA TCGA novel, REVEL 0.16, AlphaMissense 0.81, Variant assessed as somatic; moderate impact.
- A23P (p.Ala23Pro), gnomAD rs1740006250, REVEL 0.23, AlphaMissense 0.71
- A23S (p.Ala23Ser), rs1740006250, ClinGen CA359706811, ClinVar RCV006563185, REVEL 0.21, AlphaMissense 0.71, Uncertain significance, Early-infantile DEE
- A23V (p.Ala23Val), rs1060500096, ClinGen CA16611998, ClinVar RCV006606409, 1000Genomes rs1060500096, REVEL 0.23, CADD 17.50, Benign, Early-infantile DEE
- K24E (p.Lys24Glu), cosmic curated COSV57540, gnomAD rs1316303062, REVEL 0.25, CADD 19.40, Uncertain significance, Early-infantile DEE
- K24N (p.Lys24Asn), rs2478645008, ClinGen CA359706802, ClinVar RCV006561794, REVEL 0.20, CADD 18.20, Uncertain significance, Early-infantile DEE
- K24T (p.Lys24Thr), rs2478645011, ClinGen CA359706805, ClinVar RCV006563499, Uncertain significance, Early-infantile DEE
- A25E (p.Ala25Glu), rs1469192494, ClinGen CA359706797, ClinVar RCV001336535, ClinVar RCV004978354, REVEL 0.21, CADD 15.70, Conflicting interpretations, not specified; Developmental and epileptic encephalopathy, 24; Early-infantile D
- A25G (p.Ala25Gly), TOPMed rs1469192494, Likely benign
- A25V (p.Ala25Val), NCI-TCGA TCGA novel, REVEL 0.24, CADD 19.40, Variant assessed as somatic; moderate impact.
- A27G (p.Ala27Gly), TOPMed rs1461851528, gnomAD rs1461851528, REVEL 0.26, CADD 16.20
- A27T (p.Ala27Thr), rs1740005870, ClinGen CA359706788, ClinVar RCV006465177, Ensembl rs1740005870, REVEL 0.29, AlphaMissense 0.21, Uncertain significance, Early-infantile DEE
- A27V (p.Ala27Val), TOPMed rs1461851528, gnomAD rs1461851528, REVEL 0.24, CADD 16.80
- T28M (p.Thr28Met), Ensembl rs2112109678, REVEL 0.32, CADD 16.90
- G29V (p.Gly29Val), TOPMed rs1391977771, gnomAD rs1391977771, REVEL 0.31, AlphaMissense 0.16
- A30S (p.Ala30Ser), TOPMed rs1740005445, REVEL 0.22, AlphaMissense 0.14
- A30V (p.Ala30Val), NCI-TCGA TCGA novel, gnomAD rs1740005397, REVEL 0.22, CADD 14.70, Variant assessed as somatic; moderate impact.
- G31W (p.Gly31Trp), rs2112109649, ClinGen CA359706762, ClinVar RCV006468808, Ensembl rs2112109649, REVEL 0.34, AlphaMissense 0.14, Uncertain significance, Early-infantile DEE
- P32Q (p.Pro32Gln), NCI-TCGA TCGA novel, REVEL 0.33, CADD 19.10, Variant assessed as somatic; moderate impact.
- P32R (p.Pro32Arg), ExAC rs773224896, gnomAD rs773224896, REVEL 0.30, CADD 19.60
- A33S (p.Ala33Ser), Ensembl rs2112109621, REVEL 0.20, AlphaMissense 0.14
- A34S (p.Ala34Ser), NCI-TCGA TCGA novel, REVEL 0.22, AlphaMissense 0.15, Variant assessed as somatic; moderate impact.
- A34T (p.Ala34Thr), NCI-TCGA TCGA novel, REVEL 0.16, AlphaMissense 0.10, Variant assessed as somatic; moderate impact.
- A34V (p.Ala34Val), rs1740005052, ClinGen CA359706744, cosmic curated COSV10961, ClinVar RCV006468960, REVEL 0.24, CADD 8.82, Uncertain significance, Early-infantile DEE
- A35V (p.Ala35Val), rs1344167758, ClinGen CA359706738, ClinVar RCV006564024, TOPMed rs1344167758, REVEL 0.22, CADD 17.40, Uncertain significance, Early-infantile DEE
- E36* (p.Glu36Ter), NCI-TCGA Cosmic COSV1003, AlphaMissense 0.15, MetaLR 0.83, Variant assessed as somatic; high impact.
- E36A (p.Glu36Ala), rs2112109568, ClinGen CA359706732, ClinVar RCV006468282, Ensembl rs2112109568, REVEL 0.25, CADD 16.00, Uncertain significance, Early-infantile DEE
- E36G (p.Glu36Gly), rs2112109568, ClinGen CA359706731, ClinVar RCV006468237, Ensembl rs2112109568, REVEL 0.18, CADD 18.00, Uncertain significance, Early-infantile DEE
- E36K (p.Glu36Lys), cosmic curated COSV10030, TOPMed rs1295976476, gnomAD rs1295976476, REVEL 0.27, AlphaMissense 0.10
- E36Q (p.Glu36Gln), rs1295976476, ClinGen CA359706734, ClinVar RCV006560629, REVEL 0.19, AlphaMissense 0.31, Uncertain significance, Early-infantile DEE
- K37R (p.Lys37Arg), Ensembl rs2112109564, REVEL 0.19, CADD 16.10
- R38H (p.Arg38His), rs761449013, ClinGen CA359706716, cosmic curated COSV10029, ClinVar RCV006562059, REVEL 0.19, AlphaMissense 0.19, Uncertain significance, Early-infantile DEE
- R38L (p.Arg38Leu), ExAC rs761449013, TOPMed rs761449013, gnomAD rs761449013, REVEL 0.25, AlphaMissense 0.10, Uncertain significance, Early-infantile DEE
- R38P (p.Arg38Pro), ExAC rs761449013, TOPMed rs761449013, gnomAD rs761449013, REVEL 0.26, AlphaMissense 0.08, Uncertain significance
- R38S (p.Arg38Ser), rs2112109560, ClinGen CA359706717, ClinVar RCV006468767, Ensembl rs2112109560, REVEL 0.23, CADD 13.20, Uncertain significance, Early-infantile DEE
- L39Q (p.Leu39Gln), rs2478644839, ClinGen CA359706713, ClinVar RCV003135527, REVEL 0.30, CADD 16.80, Uncertain significance, not provided
- T41P (p.Thr41Pro), TOPMed rs1740004479
- T41S (p.Thr41Ser), TOPMed rs1740004479
- P42Q (p.Pro42Gln), NCI-TCGA TCGA novel, REVEL 0.33, CADD 18.80, Variant assessed as somatic; moderate impact.
- P42S (p.Pro42Ser), rs56164833, ClinGen CA16611919, ClinVar RCV000513246, ClinVar RCV002318494, REVEL 0.35, CADD 19.70, Benign/Likely benign, Early-infantile DEE; not provided; Inborn genetic diseases
- P43L (p.Pro43Leu), rs1060500095, ClinGen CA16612082, ClinVar RCV006462848, gnomAD rs1060500095, REVEL 0.29, AlphaMissense 0.11, Likely benign, Early-infantile DEE
- P43Q (p.Pro43Gln), rs1060500095, ClinGen CA359706690, ClinVar RCV006562521, gnomAD rs1060500095, REVEL 0.32, AlphaMissense 0.10, Uncertain significance, Early-infantile DEE
- G44R (p.Gly44Arg), rs1421975269, TOPMed rs1421975269, gnomAD rs1421975269, ClinGen CA359706688, REVEL 0.34, AlphaMissense 0.08, Uncertain significance, Early-infantile DEE
- G44W (p.Gly44Trp), rs1421975269, ClinGen CA359706687, ClinVar RCV003237659, ClinVar RCV006557702, REVEL 0.36, AlphaMissense 0.07, Uncertain significance, Early-infantile DEE; not provided
- G45A (p.Gly45Ala), TOPMed rs1740003977, gnomAD rs1740003977, REVEL 0.23, AlphaMissense 0.07
- G45D (p.Gly45Asp), TOPMed rs1740003977, gnomAD rs1740003977, REVEL 0.27, AlphaMissense 0.17
- G46C (p.Gly46Cys), rs1031913850, ClinGen CA359706675, ClinVar RCV002384526, ClinVar RCV006466736, REVEL 0.38, AlphaMissense 0.14, Uncertain significance, Early-infantile DEE; Inborn genetic diseases
- G46R (p.Gly46Arg), TOPMed rs1031913850, gnomAD rs1031913850, REVEL 0.35, AlphaMissense 0.42, Uncertain significance
- G46S (p.Gly46Ser), TOPMed rs1031913850, gnomAD rs1031913850, REVEL 0.28, AlphaMissense 0.08, Uncertain significance, Inborn genetic diseases
- G47R (p.Gly47Arg), rs2478644562, ClinGen CA359706671, ClinVar RCV006562272, REVEL 0.25, CADD 16.90, Uncertain significance, Early-infantile DEE
- G47V (p.Gly47Val), rs544994462, ClinGen CA238962, cosmic curated COSV57523, ClinVar RCV000173511, REVEL 0.38, CADD 16.50, Benign/Likely benign, Early-infantile DEE; not provided; not specified
- A48S (p.Ala48Ser), Ensembl rs866992298, REVEL 0.23, CADD 7.70
- A48V (p.Ala48Val), TOPMed rs1415475910, REVEL 0.28, CADD 14.30
- G49S (p.Gly49Ser), rs1214766208, ClinGen CA359706659, cosmic curated COSV10030, ClinVar RCV006560573, REVEL 0.24, AlphaMissense 0.19, Uncertain significance, Early-infantile DEE
- A50T (p.Ala50Thr), gnomAD rs1462816724, REVEL 0.20, AlphaMissense 0.07
- A50V (p.Ala50Val), rs2478644516, ClinGen CA359706650, ClinVar RCV006559538, REVEL 0.21, AlphaMissense 0.09, Uncertain significance, Early-infantile DEE
- H53P (p.His53Pro), rs1554040137, ClinGen CA359706628, ClinVar RCV006607366, gnomAD rs1554040137, AlphaMissense 0.08, MetaLR 0.72, Uncertain significance, Early-infantile DEE
- H53Q (p.His53Gln), rs10066808, ClinGen CA359706627, ClinVar RCV004723367, ClinVar RCV006562087, REVEL 0.27, CADD 5.85, Conflicting interpretations, Inborn genetic diseases; Early-infantile DEE; not specified
- H53Y (p.His53Tyr), rs1467006341, ClinGen CA359706631, ClinVar RCV002392644, TOPMed rs1467006341, REVEL 0.29, AlphaMissense 0.07, Uncertain significance, Inborn genetic diseases
- G54C (p.Gly54Cys), TOPMed rs1245405853, gnomAD rs1245405853, REVEL 0.38, CADD 23.00, Uncertain significance
- G54D (p.Gly54Asp), TOPMed rs1391013594, REVEL 0.31, AlphaMissense 0.09
- G54R (p.Gly54Arg), rs1245405853, ClinGen CA359706625, ClinVar RCV001266029, ClinVar RCV006557291, REVEL 0.33, CADD 15.30, Uncertain significance, Inborn genetic diseases; Early-infantile DEE
- S56T (p.Ser56Thr), rs2478644460, ClinGen CA359706612, ClinVar RCV006563446, REVEL 0.43, CADD 23.30, Uncertain significance, Early-infantile DEE
- V57M (p.Val57Met), cosmic curated COSV10814, Ensembl rs1740002750, REVEL 0.43, CADD 22.70
- C58G (p.Cys58Gly), Ensembl rs2112109416
- F59L (p.Phe59Leu), rs1298378220, ClinGen CA359706585, ClinVar RCV002404045, gnomAD rs1298378220, REVEL 0.40, AlphaMissense 0.99, Uncertain significance, Inborn genetic diseases
- K60Q (p.Lys60Gln), 1000Genomes rs2112109404, REVEL 0.36, AlphaMissense 0.17
- V61L (p.Val61Leu), rs900254081, ClinGen CA118329975, ClinVar RCV002554634, ClinVar RCV006465287, REVEL 0.27, AlphaMissense 0.19, Likely benign, Early-infantile DEE; Inborn genetic diseases
- V61M (p.Val61Met), rs900254081, ClinGen CA359706576, ClinVar RCV004399370, NCI-TCGA TCGA novel, AlphaMissense 0.19, MetaLR 0.71, Uncertain significance, Inborn genetic diseases
- D62N (p.Asp62Asn), gnomAD rs1275868182, REVEL 0.30, CADD 21.90
- D62V (p.Asp62Val), rs1554040136, ClinGen CA359706567, ClinVar RCV000585338, Ensembl rs1554040136, AlphaMissense 0.42, MetaLR 0.71, Uncertain significance, not provided
- G63S (p.Gly63Ser), gnomAD rs1406370096, REVEL 0.22, CADD 18.90
- G64S (p.Gly64Ser), gnomAD rs1365874820, REVEL 0.26, CADD 20.00
- G66S (p.Gly66Ser), TOPMed rs1356150414, gnomAD rs1356150414
- G67A (p.Gly67Ala), TOPMed rs941855168, REVEL 0.27, CADD 15.60
- G67R (p.Gly67Arg), rs1427664939, ClinGen CA359706538, ClinVar RCV002313570, ClinVar RCV005367523, REVEL 0.37, CADD 20.90, Uncertain significance, Inborn genetic diseases; not provided
- G67S (p.Gly67Ser), rs1427664939, ClinGen CA359706539, ClinVar RCV004981006, ClinVar RCV006563825, REVEL 0.28, CADD 19.20, Uncertain significance, Inborn genetic diseases; Early-infantile DEE
- G68D (p.Gly68Asp), rs2478644362, ClinGen CA359706530, ClinVar RCV006559624, REVEL 0.42, CADD 11.50, Uncertain significance, Early-infantile DEE
- G69S (p.Gly69Ser), gnomAD rs1201375181, REVEL 0.37, CADD 14.10
- G70D (p.Gly70Asp), rs1269949873, ClinGen CA359706519, ClinVar RCV005871196, ClinVar RCV006562085, REVEL 0.36, CADD 20.10, Uncertain significance, Generalized epilepsy with febrile seizures plus, type 10; Early-infantile DEE
- G70R (p.Gly70Arg), rs1255330911, ClinGen CA359706521, ClinVar RCV002424033, NCI-TCGA TCGA novel, AlphaMissense 0.10, MetaLR 0.77, Uncertain significance, Inborn genetic diseases
- G70S (p.Gly70Ser), TOPMed rs1255330911, REVEL 0.26, AlphaMissense 0.10
- G71D (p.Gly71Asp), gnomAD rs1487553404, REVEL 0.37, AlphaMissense 0.99
- G71R (p.Gly71Arg), ExAC rs771362022, gnomAD rs771362022, REVEL 0.42, AlphaMissense 0.99
- G71S (p.Gly71Ser), ExAC rs771362022, gnomAD rs771362022, REVEL 0.35, AlphaMissense 0.99
- G72D (p.Gly72Asp), TOPMed rs1205869080, gnomAD rs1205869080, REVEL 0.40, CADD 16.70
- G72S (p.Gly72Ser), rs2478644266, ClinGen CA359706510, ClinVar RCV006612123, REVEL 0.31, AlphaMissense 0.38, Uncertain significance, Early-infantile DEE
- G74D (p.Gly74Asp), TOPMed rs1282259414, gnomAD rs1282259414, REVEL 0.42, CADD 14.70
- G74R (p.Gly74Arg), ExAC rs747284102, gnomAD rs747284102, REVEL 0.39, CADD 15.90
- G74V (p.Gly74Val), TOPMed rs1282259414, gnomAD rs1282259414, REVEL 0.44, CADD 15.30
- E75D (p.Glu75Asp), rs2112109170, ClinGen CA359706488, ClinVar RCV006558090, Ensembl rs2112109170, REVEL 0.21, CADD 6.35, Uncertain significance, Early-infantile DEE
- E75K (p.Glu75Lys), rs1374925949, gnomAD rs1374925949, REVEL 0.30, CADD 20.50, Uncertain significance
- E75Q (p.Glu75Gln), rs1374925949, ClinGen CA359706493, ClinVar RCV002274573, gnomAD rs1374925949, REVEL 0.27, CADD 18.50, Uncertain significance, not provided
- P77A (p.Pro77Ala), Ensembl rs1561248449
- P77L (p.Pro77Leu), rs1348079874, NCI-TCGA Cosmic COSV5751, cosmic curated COSV57514, TOPMed rs1348079874, REVEL 0.30, CADD 19.40, Variant assessed as somatic; moderate impact.
- P77Q (p.Pro77Gln), TOPMed rs1348079874, gnomAD rs1348079874, REVEL 0.27, CADD 17.60
- P77T (p.Pro77Thr), Ensembl rs1561248449, REVEL 0.18, AlphaMissense 0.96
- A78S (p.Ala78Ser), ESP rs376072704, ExAC rs376072704, TOPMed rs376072704, gnomAD rs376072704, REVEL 0.21, CADD 8.53, Uncertain significance
- A78T (p.Ala78Thr), rs376072704, ClinGen CA3259494, cosmic curated COSV57496, ClinVar RCV002457620, REVEL 0.20, CADD 12.20, Uncertain significance, Inborn genetic diseases
- A78V (p.Ala78Val), gnomAD rs1178320320, REVEL 0.20, CADD 15.20
- G79R (p.Gly79Arg), rs2478644134, ClinGen CA359706467, ClinVar RCV006471521, REVEL 0.20, CADD 13.30, Likely benign, Early-infantile DEE
- G79V (p.Gly79Val), gnomAD rs1430178931
- G80A (p.Gly80Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G80C (p.Gly80Cys), rs754990881, ClinGen CA359706460, cosmic curated COSV10030, ClinVar RCV006465929, REVEL 0.34, CADD 19.80, Uncertain significance, Early-infantile DEE
- G80D (p.Gly80Asp), rs1252720341, ClinGen CA359706459, ClinVar RCV000594451, ClinVar RCV006463483, REVEL 0.24, CADD 18.10, Uncertain significance, Early-infantile DEE; not provided
- G80S (p.Gly80Ser), ExAC rs754990881, gnomAD rs754990881, REVEL 0.19, CADD 13.80, Uncertain significance
- F81I (p.Phe81Ile), NCI-TCGA Cosmic COSV5754, cosmic curated COSV57542, Variant assessed as somatic; moderate impact.
- F81L (p.Phe81Leu), rs2112109104, ClinGen CA359706450, ClinVar RCV006557974, Ensembl rs2112109104, REVEL 0.25, CADD 0.85, Likely benign, Early-infantile DEE
- F81Y (p.Phe81Tyr), rs886043302, ClinGen CA10605354, ClinVar RCV000292789, gnomAD rs886043302, REVEL 0.21, CADD 11.80, Uncertain significance, not provided
- E82K (p.Glu82Lys), NCI-TCGA Cosmic COSV5751, cosmic curated COSV57517, REVEL 0.26, CADD 19.10, Variant assessed as somatic; moderate impact.
- D83E (p.Asp83Glu), TOPMed rs1739999039, REVEL 0.38, CADD 13.90, Uncertain significance, HCN1-related disorder
- D83Y (p.Asp83Tyr), NCI-TCGA Cosmic COSV1003, cosmic curated COSV10030, Variant assessed as somatic; moderate impact.
- A84S (p.Ala84Ser), gnomAD rs1256720723, REVEL 0.33, CADD 17.80
- E85* (p.Glu85Ter), NCI-TCGA Cosmic COSV5752, cosmic curated COSV57525, AlphaMissense 0.85, MetaLR 0.71, Uncertain significance, in GEFSP10
- E85A (p.Glu85Ala), UniProt VAR 082653, Uncertain significance, in GEFSP10
- E85D (p.Glu85Asp), rs868228427, ClinGen CA10605797, cosmic curated COSV57531, ClinVar RCV000288763, REVEL 0.29, CADD 19.50, Uncertain significance, Early-infantile DEE; not provided
- E85K (p.Glu85Lys), cosmic curated COSV10514, gnomAD rs1739998877, REVEL 0.34, AlphaMissense 1.00, Uncertain significance, in GEFSP10
- G86E (p.Gly86Glu), TOPMed rs1230569941, gnomAD rs1230569941, REVEL 0.30, CADD 15.40, Uncertain significance, Early-infantile DEE
- G86R (p.Gly86Arg), rs760568557, ClinGen CA3259488, ClinVar RCV005572351, ClinVar RCV006609623, REVEL 0.45, AlphaMissense 1.00, Conflicting interpretations, Inborn genetic diseases; Early-infantile DEE
- G86V (p.Gly86Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- P87H (p.Pro87His), rs1397144091, NCI-TCGA Cosmic COSV1003, cosmic curated COSV10030, Ensembl rs1397144091, REVEL 0.30, CADD 22.70, Variant assessed as somatic; moderate impact.
- P87S (p.Pro87Ser), rs370113959, ClinGen CA3259486, cosmic curated COSV10029, ClinVar RCV002316539, REVEL 0.24, CADD 17.90, Benign/Likely benign, Early-infantile DEE; Inborn genetic diseases
- P87T (p.Pro87Thr), 1000Genomes rs370113959, ESP rs370113959, ExAC rs370113959, TOPMed rs370113959, REVEL 0.24, CADD 18.20, Benign
- R88G (p.Arg88Gly), rs774375241, ClinGen CA3259484, ClinVar RCV006466636, ExAC rs774375241, REVEL 0.29, CADD 22.60, Likely benign, Early-infantile DEE
- R88L (p.Arg88Leu), rs1173138693, ClinGen CA359706407, ClinVar RCV006558149, TOPMed rs1173138693, AlphaMissense 0.09, MetaLR 0.68, Uncertain significance, Early-infantile DEE
- R88Q (p.Arg88Gln), TOPMed rs1173138693, gnomAD rs1173138693, REVEL 0.26, AlphaMissense 0.09, Uncertain significance
- R89Q (p.Arg89Gln), rs1739997928, ClinGen CA359706403, cosmic curated COSV10030, ClinVar RCV006464728, REVEL 0.29, CADD 20.30, Uncertain significance, Early-infantile DEE
- Q90K (p.Gln90Lys), rs2112109013, ClinGen CA2573139746, ClinVar RCV006469423, Ensembl rs2112109013, REVEL 0.30, AlphaMissense 0.82, Likely benign, Early-infantile DEE
- Y91* (p.Tyr91Ter), rs1170637860, ClinGen CA359706388, cosmic curated COSV57521, ClinVar RCV001754127, Uncertain significance
- Y91C (p.Tyr91Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Y91F (p.Tyr91Phe), NCI-TCGA TCGA novel, Ensembl rs1739997647, Variant assessed as somatic; moderate impact.
- G92C (p.Gly92Cys), TOPMed rs1413239994, gnomAD rs1413239994, REVEL 0.73, AlphaMissense 0.71
- G92R (p.Gly92Arg), TOPMed rs1413239994, gnomAD rs1413239994
- G92S (p.Gly92Ser), rs1413239994, ClinGen CA359706385, ClinVar RCV006562218, NCI-TCGA Cosmic COSV5751, AlphaMissense 0.71, MetaLR 0.90, Uncertain significance, Early-infantile DEE
- F93L (p.Phe93Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- M94I (p.Met94Ile), rs748665278, ExAC rs748665278, TOPMed rs748665278, gnomAD rs748665278, REVEL 0.42, CADD 20.90, Conflicting interpretations, not specified; Developmental and epileptic encephalopathy, 24; Early-infantile D
- M94K (p.Met94Lys), ExAC rs772623522, gnomAD rs772623522, REVEL 0.68, CADD 25.60
- M94V (p.Met94Val), rs773441535, ClinGen CA3259478, ClinVar RCV004972888, ClinVar RCV006463978, REVEL 0.39, AlphaMissense 0.78, Conflicting interpretations, Early-infantile DEE; Inborn genetic diseases
- Q95E (p.Gln95Glu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Q95H (p.Gln95His), TOPMed rs980130181, gnomAD rs980130181, REVEL 0.38, CADD 17.60
- R96K (p.Arg96Lys), rs1739997160, ClinGen CA359706357, ClinVar RCV003135528, TOPMed rs1739997160, AlphaMissense 0.30, MetaLR 0.80, Uncertain significance, not provided
- Q97E (p.Gln97Glu), NCI-TCGA Cosmic COSV5751, Variant assessed as somatic; moderate impact.
- Q97K (p.Gln97Lys), rs2478643901, ClinGen CA359706352, ClinVar RCV002511389, Uncertain significance, not provided
- Q97R (p.Gln97Arg), rs1580055035, ClinGen CA359706348, ClinVar RCV000998381, ClinVar RCV006464942, REVEL 0.70, CADD 26.40, Uncertain significance, not provided; Early-infantile DEE
- F98C (p.Phe98Cys), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10029, Variant assessed as somatic; moderate impact.
- F98L (p.Phe98Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- T99G (p.Thr99Gly), rs1739996970, ClinGen CA916082709, ClinVar RCV001054782, Ensembl rs1739996970, Uncertain significance, Developmental and epileptic encephalopathy
- T99I (p.Thr99Ile), cosmic curated COSV57530, 1000Genomes rs143865339, ESP rs143865339, ExAC rs143865339, REVEL 0.17, CADD 19.30
- T99P (p.Thr99Pro), ExAC rs779325604, REVEL 0.28, CADD 22.90
- T99S (p.Thr99Ser), rs143865339, ClinGen CA359706333, ClinVar RCV003152084, REVEL 0.11, CADD 16.90, Uncertain significance, not provided
- S100A (p.Ser100Ala), rs780364002, ClinGen CA3259471, ClinVar RCV006609001, ExAC rs780364002, REVEL 0.22, CADD 16.40, Likely benign, Early-infantile DEE
- S100F (p.Ser100Phe), rs587777492, ClinGen CA163272, NCI-TCGA Cosmic COSV5751, cosmic curated COSV57516, REVEL 0.86, CADD 25.80, Pathogenic/Likely pathogenic, Generalized epilepsy with febrile seizures plus, type 10; Early-infantile DEE; n
- S100P (p.Ser100Pro), ExAC rs780364002, TOPMed rs780364002, gnomAD rs780364002, REVEL 0.42, CADD 25.30, Likely benign, in DEE24
- M101I (p.Met101Ile), rs1456742212, ClinGen CA359706321, ClinVar RCV002280501, ClinGen CA359706322, REVEL 0.42, CADD 23.60, Uncertain significance, not provided
- M101L (p.Met101Leu), TOPMed rs1739996550, gnomAD rs1739996550, REVEL 0.28, AlphaMissense 0.95, Uncertain significance
- M101V (p.Met101Val), rs1739996550, ClinGen CA359706328, ClinVar RCV006557935, TOPMed rs1739996550, REVEL 0.49, AlphaMissense 0.85, Uncertain significance, Early-infantile DEE
- L102Q (p.Leu102Gln), rs886042909, ClinGen CA10604848, ClinVar RCV000383662, Ensembl rs886042909, AlphaMissense 0.99, MetaLR 0.74, Uncertain significance, not provided
- P104S (p.Pro104Ser), NCI-TCGA Cosmic COSV1003, cosmic curated COSV10030, Variant assessed as somatic; moderate impact.
Public HCN1 analysis runs
- HCN1 analysis run — HCN1 (1,814 variants) — completed 2026-07-07